Evaluation of methamphetamine assist packs: As-needed antipsychotics for self-management of methamphetamine-associated psychiatric toxicity.

BACKGROUND: Methamphetamine frequently causes substance-induced psychosis and related symptoms. There are currently no interventions to prevent or assist in self-management of these symptoms. METHODS: We evaluated a program providing "Methamphetamine Assist Packs" to patients who were seen in a psychiatric emergency services program for methamphetamine-induced psychosis. Methamphetamine Assist Packs included a small number of tablets of an antipsychotic medication (olanzapine), administration instructions, and referral information. We reviewed medical charts of patients who received Methamphetamine Assist Packs from January 2022 through May 2023 for sociodemographic and emergency visit characteristics. We assessed the changes between the number of psychiatric emergency visits before and after Methamphetamine Assist Pack receipt at two, six, and 12 months using generalized estimating equations. RESULTS: Ninety-two patients received a Methamphetamine Assist Pack, with a mean age of 40 years; 79 % were male and 49 % Black/African American; 77 % experienced housing instability or homelessness. The most common symptoms were suicidal ideation (54 %), paranoia or delusions (45 %), and hallucinations (40 %); 55 % were on involuntary psychiatric hold, 38 % required medications for agitation, and 18 % required seclusion or physical restraints. The rate of psychiatric emergency visits after Methamphetamine Assist Pack receipt was 0.68 and 0.87 times the rate prior to receipt at two and six months, respectively (p < 0.001). There was no difference at 12 months. CONCLUSIONS: Methamphetamine Assist Packs were associated with fewer psychiatric emergency visits for six months after receipt, and represent a promising intervention to address acute psychiatric toxicity from methamphetamine in need of further research.

Impact of Hearing Aids on Language Outcomes in Preschool Children With Mild Bilateral Hearing Loss.

This study aimed to investigate the role of hearing aid (HA) usage in language outcomes among preschool children aged 3-5 years with mild bilateral hearing loss (MBHL). The data were retrieved from a total of 52 children with MBHL and 30 children with normal hearing (NH). The association between demographical, audiological factors and language outcomes was examined. Analyses of variance were conducted to compare the language abilities of HA users, non-HA users, and their NH peers. Furthermore, regression analyses were performed to identify significant predictors of language outcomes. Aided better ear pure-tone average (BEPTA) was significantly correlated with language comprehension scores. Among children with MBHL, those who used HA outperformed the ones who did not use HA across all linguistic domains. The language skills of children with MBHL were comparable to those of their peers with NH. The degree of improvement in audibility in terms of aided BEPTA was a significant predictor of language comprehension. It is noteworthy that 50% of the parents expressed reluctance regarding HA use for their children with MBHL. The findings highlight the positive impact of HA usage on language development in this population. Professionals may therefore consider HAs as a viable treatment option for children with MBHL, especially when there is a potential risk of language delay due to hearing loss. It was observed that 25% of the children with MBHL had late-onset hearing loss. Consequently, the implementation of preschool screening or a listening performance checklist is recommended to facilitate early detection.

Altered transcriptomic immune responses of maintenance hemodialysis patients to the COVID-19 mRNA vaccine.

Background: End-stage renal disease (ESRD) patients experience immune compromise characterized by complex alterations of both innate and adaptive immunity, and results in higher susceptibility to infection and lower response to vaccination. This immune compromise, coupled with greater risk of exposure to infectious disease at hemodialysis (HD) centers, underscores the need for examination of the immune response to the COVID-19 mRNA-based vaccines. Methods: The immune response to the COVID-19 BNT162b2 mRNA vaccine was assessed in 20 HD patients and cohort-matched controls. RNA sequencing of peripheral blood mononuclear cells was performed longitudinally before and after each vaccination dose for a total of six time points per subject. Anti-spike antibody levels were quantified prior to the first vaccination dose (V1D0) and 7 d after the second dose (V2D7) using anti-spike IgG titers and antibody neutralization assays. Anti-spike IgG titers were additionally quantified 6 mo after initial vaccination. Clinical history and lab values in HD patients were obtained to identify predictors of vaccination response. Results: Transcriptomic analyses demonstrated differing time courses of immune responses, with prolonged myeloid cell activity in HD at 1 wk after the first vaccination dose. HD also demonstrated decreased metabolic activity and decreased antigen presentation compared to controls after the second vaccination dose. Anti-spike IgG titers and neutralizing function were substantially elevated in both controls and HD at V2D7, with a small but significant reduction in titers in HD groups (p<0.05). Anti-spike IgG remained elevated above baseline at 6 mo in both subject groups. Anti-spike IgG titers at V2D7 were highly predictive of 6-month titer levels. Transcriptomic biomarkers after the second vaccination dose and clinical biomarkers including ferritin levels were found to be predictive of antibody development. Conclusions: Overall, we demonstrate differing time courses of immune responses to the BTN162b2 mRNA COVID-19 vaccination in maintenance HD subjects comparable to healthy controls and identify transcriptomic and clinical predictors of anti-spike IgG titers in HD. Analyzing vaccination as an in vivo perturbation, our results warrant further characterization of the immune dysregulation of ESRD. Funding: F30HD102093, F30HL151182, T32HL144909, R01HL138628. This research has been funded by the University of Illinois at Chicago Center for Clinical and Translational Science (CCTS) award UL1TR002003.

A care coordination program to support patients with hepatitis B virus at Kaiser Permanente Mid-Atlantic States.

BACKGROUND: Eliminating hepatitis B virus (HBV) is a significant worldwide challenge requiring innovative approaches for vaccination, screening, disease management, and the prevention of related conditions. Programs that support patients in accessing needed clinical services can help optimize access to preventive services and treatment resources for hepatitis B. METHODS: Here, we outline a coordinator-supported program (HBV Pathway) that connects patients infected with HBV to laboratory testing, imaging, and specialty care for treatment initiation and/or liver cancer surveillance (screening of high-risk patients for liver cancer). This study describes the HBV Pathway steps and reports sociodemographic factors of patients by initiation and completion. RESULTS: Results showed a 72.5% completion rate (defined as completing all Pathway steps including the final specialty visit) among patients who initiated the Pathway. Differences in completion were observed by age, race, ethnicity, and service area, with higher rates for younger ages, Asian race, non-Hispanic ethnicity, and lower rates for patients within one service area. Of those who completed the specialty visit, 59.5% were referred for hepatocellular carcinoma surveillance. CONCLUSIONS: The HBV Pathway offers dual benefits- care coordination support for patients to promote Pathway completion and a standardized testing and referral program to reduce physician burden. This program provides an easy and reliable process for patients and physicians to obtain updated clinical information and initiate treatment and/or liver cancer screening if needed.

Perception and Correlates of Opioid Overdose Risk Among Overdose Survivors Who Use Nonprescribed Opioids in San Francisco and Boston.

BACKGROUND: Understanding opioid overdose risk perception may inform overdose prevention strategies. METHODS: We used baseline data from a randomized overdose prevention trial, in San Francisco, CA, and Boston, MA, among people who used nonprescribed opioids, survived an overdose in the past 3 years, and had received naloxone. Participants were asked how likely they were to overdose in the next 4 months. We combined "extremely likely" and "likely" (higher risk perception) and "neutral," "unlikely," and "extremely unlikely" (lower risk perception). We performed bivariate analyses and separate multivariable logistic regression models of risk perception across (1) sociodemographic, (2) substance use, and (3) overdose risk behavior measures. Covariates were selected a priori or significant in bivariate analyses. RESULTS: Among 268 participants, 88% reported at least 1 overdose risk behavior; however, only 21% reported higher risk perception. The adjusted odds ratio (AOR) of higher risk perception was 2.41 (95% confidence interval [CI]: 1.10-5.30) among those unhoused in the past 4 months, 2.06 (95% CI: 1.05-4.05) among those using opioids in a new place, and 5.61 (95% CI: 2.82-11.16) among those who had overdosed in the past 4 months. Living in Boston was associated with higher risk perception in all 3 models (AOR = 2.00-2.46, 95% CI: 1.04-4.88). CONCLUSIONS: Despite prevalent risk behaviors, a minority of participants perceived themselves to be at higher risk of overdose. Nonetheless, some known risk factors for overdose were appropriately associated with risk perception. Fentanyl has been prevalent in Boston for longer than San Francisco, which may explain the higher risk perception there.

Accidental substance-related acute toxicity deaths among youth in Canada: a descriptive analysis of a national chart review study of coroner and medical examiner data. / Décès accidentels attribuables à une intoxication aiguë due à une substance chez les jeunes au Canada : analyse descriptive d'une étude nationale portant sur l'examen des dossiers des données de coroners et de médecins légistes.

INTRODUCTION: Substance-related acute toxicity deaths (ATDs) are a public health crisis in Canada. Youth are often at higher risk for substance use due to social, environmental and structural factors. The objectives of this study were to understand the characteristics of youth (aged 12-24 years) dying of accidental acute toxicity in Canada and examine the substances contributing to and circumstances surrounding youth ATDs. METHODS: Data from a national chart review study of coroner and medical examiner data on ATDs that occurred in Canada between 2016 and 2017 were used to conduct descriptive analyses with proportions, mortality rates and proportionate mortality rates. Where possible, youth in the chart review study were compared with youth in the general population and youth who died of all causes, using census data. RESULTS: Of the 732 youth who died of accidental acute toxicity in 2016-2017, most (94%) were aged 18 to 24 years. Youth aged 20 to 24 who were unemployed, unhoused or living in collective housing were overrepresented among accidental ATDs. Many of the youth aged 12 to 24 who died of accidental acute toxicity had a documented history of substance use. Fentanyl, cocaine and methamphetamine were the most common substances contributing to death, and 38% of the deaths were witnessed or potentially witnessed. CONCLUSION: The findings of this study point to the need for early prevention and harm reduction strategies and programs that address mental health, exposure to trauma, unemployment and housing instability to reduce the harms of substance use on Canadian youth.

Effect of sample length on MLU in Mandarin-speaking hard-of-hearing children.

This study investigated the impact of language sample length on mean length of utterance (MLU) and aimed to determine the minimum number of utterances required for a reliable MLU. Conversations were collected from Mandarin-speaking, hard-of-hearing and typical-hearing children aged 16-81 months. The MLUs were calculated using sample sizes ranging from 25 to 200 utterances. The results showed that for an MLU between 1.0 and 2.5, 25 and 50 utterances were sufficient for reliable MLU calculations for hard-of-hearing and typical-hearing children, respectively. For an MLU between 2.5 and 3.75, 125 utterances were required for both groups. For an MLU greater than 3.75, 150 and 125 utterances were required for hard-of-hearing and typical-hearing children, respectively. These findings suggest that a greater number of utterances are required for a reliable MLU as language complexity increases. Professionals working with hard-of-hearing children should consider collecting different numbers of utterances based on the children's language complexity levels.

Hearing aid wear time and its impact on vocabulary in preschoolers with moderately severe to profound hearing loss.

OBJECTIVE: This study aimed to explore how the consistency of hearing aid (HA) use impacts vocabulary performance in children with moderately severe to profound hearing loss and determine the amount of HA use time associated with better vocabulary outcomes. DESIGN: Personal wear time percentage (WTP) was an indicator of HA use consistency, and the information on HA wear time was collected from both parent reports and datalogs. Pearson's correlations were performed to investigate the associations between hearing loss severity, WTP and vocabulary performance. Standard vocabulary scores among children below and above three WTP cutoff values (80%, 85%, and 90%) were examined to determine the WTP amount that yielded significantly better vocabulary outcomes. STUDY SAMPLE: Forty-seven children aged 36-79 months and their caregivers. RESULTS: Both parent reports and datalogs WTP significantly correlated with vocabulary outcomes. Parent-reported WTP were found to be predictive of datalogs WTP. Apart from hearing thresholds, HA fitting age and maternal education level, datalogs WTP was a significant independent predictor of vocabulary performance. Children with ≥ 90% WTP were more likely to perform better on vocabulary tests than those with < 90% WTP. CONCLUSION: The findings support the potential benefits of consistent HA use for vocabulary development.

Plant-derived galactolipids enhance specific antibody production and induce class-switch as vaccine adjuvant.

Various plant-derived compounds can activate immune responses against bacterial infections, and this property contributes to them being developed as effective and safe adjuvants for vaccines. This study evaluated the potential adjuvant effects of a galactolipid-enriched fraction generated from the medicinal plant Crassocephalum rabens (designated CRA). Heat shock protein 60 of periodontal disease pathogen Actinobacillus actinomycetemcomitans (AaHSP60) was taken as an antigen and mixed with CRA. The AaHSP60/CRA mixture was then injected intraperitoneally into the BALB/c mice. Titers and affinity of specific antibodies were measured by ELISA. Cytokine profiles in mouse serum or culture media of AaHSP60/CRA-treated splenocytes were analyzed by cytokine multiplex assay and ELISA kits. B cell differentiation and macrophage activation were determined by phenotyping. CRA dramatically enhanced specific antibody titers and induced Ig class switch, as shown by increases in the IgG2a, IgG2b, and IgG3 proportions of total Ig in mouse serum. Furthermore, CRA-induced anti-AaHSP60 antibodies had cross-reactivity to other bacterial HSP60s. Cell-based and animal results demonstrated that CRA induced the release of IL-21 and B cell activating factor (BAFF), which stimulated B cell differentiation. CRA enhanced cell proliferation, uptake ability, and antigen presentation in mouse phagocytes. CRA served as a vaccine adjuvant that enhance mouse immunity against pathogenic antigens. CRA strengthened the activation and capabilities of phagocytes and B cells. Therefore, CRA may be a promising adjuvant for bacterial vaccines including periodontal disease.

Disrupted executive cerebro-cerebellar functional connectivity in alcohol use disorder.

BACKGROUND: Alcohol use disorder (AUD) affects 283 million people worldwide and its prevalence is increasing. Despite the role of the cerebellum in executive control and its sensitivity to alcohol, few studies have assessed its involvement in AUD-relevant functional networks. The goal of this study is to compare resting-state functional connectivity (FC) patterns in abstinent adults with a history of AUD and controls (CTL). We hypothesized that group differences in cerebro-cerebellar FC would be present, particularly within the frontoparietal/executive control network (FPN). METHODS: Twenty-eight participants completed a resting-state functional magnetic resonance imaging (rsfMRI) study. CTL participants had no history of AUD, comorbid psychological conditions, or recent heavy drinking and/or drug use. AUD participants had a history of AUD, with sobriety for at least 30 days prior to data collection. Multivariate pattern analysis, an agnostic, whole-brain approach, was used to identify regions with significant differences in FC between groups. Seed-based analyses were then conducted to determine the directionality and extent of these FC differences. Associations between FC strength and executive function were assessed using correlations with Wisconsin Card Sorting Test (WCST) performance. RESULTS: There were significant group differences in FC in nodes of the FPN, ventral attention network, and default mode network. Post hoc analyses predominantly identified FC differences within the cerebro-cerebellar FPN, with AUD showing significantly less FC within the FPN. In AUD, FC strength between FPN clusters identified in the multivariate pattern analysis (MVPA) analysis (Left Crus II, Right Frontal Cortex) was positively associated with performance on the WCST. CONCLUSIONS: Our results show less engagement of the FPN in individuals with AUD than in CTL. FC strength within this network was positively associated with performance on the WCST. These findings suggest that long-term heavy drinking alters cerebro-cerebellar FC, particularly within networks that are involved in executive function.

COVID-19 and Adolescent Outpatient Mental Health Service Utilization.

OBJECTIVE: The COVID-19 pandemic created challenges in accessing mental health (MH) services when adolescent well-being declined. Still, little is known about how the COVID-19 pandemic affected outpatient MH service utilization for adolescents. METHODS: Retrospective data were collected from electronic medical records of adolescents aged 12-17 years at Kaiser Permanente Mid-Atlantic States, an integrated health care system from January 2019 to December 2021. MH diagnoses included anxiety, mood disorder/depression, anxiety and mood disorder/depression, attention-deficit/hyperactivity disorder, or psychosis. We used interrupted time series analysis to compare MH visits and psychopharmaceutical prescribing before and after the COVID-19 onset. Analyses were stratified by demographics and visit modality. RESULTS: The study population of 8121 adolescents with MH visits resulted in a total of 61,971 (28.1%) of the 220,271 outpatient visits associated with an MH diagnosis. During 15,771 (7.2%) adolescent outpatient visits psychotropic medications were prescribed. The increasing rate of MH visits prior to COVID-19 was unaffected by COVID-19 onset; however, in-person visits declined by 230.5 visits per week (P < .001) from 274.5 visits per week coupled with a rise in virtual modalities. Rates of MH visits during the COVID-19 pandemic differed by sex, mental health diagnosis, and racial and ethnic identity. Psychopharmaceutical prescribing during MH visits declined beyond expected values by a mean of 32.8 visits per week (P < .001) at the start of the COVID-19 pandemic. CONCLUSIONS: A sustained switch to virtual visits highlights a new paradigm in care modalities for adolescents. Psychopharmaceutical prescribing declined requiring further qualitative assessments to improve the quality of access for adolescent MH.

Pride Medical at Capitol Hill: A New Lesbian, Gay, Bisexual, Transgender, Queer/Questioning plus (LGBTQ+) Patient Care Option at Kaiser Permanente Mid-Atlantic States.

When accessing medical care, lesbian, gay, bisexual, transgender, queer/questioning plus (LGBTQ+) individuals face many known challenges, including stigma, discrimination, and health disparities. Transgender and nonbinary individuals often encounter physicians and staff who are not knowledgeable about gender-affirming services and the transition journey. Finding an affirming physician can be a trial-and-error process, causing concern and uncertainty. In 2021, Kaiser Permanente Mid-Atlantic States (KPMAS) researchers published a study examining the gaps in care and experience for transgender and nonbinary patients within the KPMAS healthcare system. KPMAS realized an opportunity to both close the gaps in care identified by transgender and nonbinary patients and enhance services for the broader LGBTQ+ patient community by creating Pride Medical at Capitol Hill-an additional and optional care site for individuals who identify as LGBTQ+. During the analysis timeframe of 30 June 2021 through 30 November 2022, 586 patients accessed care through 763 visits. A total of 675 visits (88%) were for primary care and 88 (12%) for OB/GYN. Over 50% (n = 384) of total visits were conducted virtually. The plurality of patients seen identified as a man (35%; n = 204) and gay (30%; n = 176). Postvisit survey results showed that 92% of survey respondents strongly agreed that the physician treated them with courtesy and respect, and 72% of survey respondents rated their overall care as excellent. Survey results show high acceptability of this program among the patients served. Pride Medical does not carve out care. The program offers patients access to a more specialized team of physicians-a similar model to other specialties-that is easily found by the division name Pride Medical. Layering additional specialty divisions on top of existing care, for interested patients, could be an option for other medical groups and health systems seeking to offer additional options of care for interested LGBTQ+ patients.

Immunotherapy for ovarian cancer is improved by tumor targeted delivery of a neoantigen surrogate.

Ovarian cancer is known for its poor neoantigen expression and strong immunosuppression. Here, we utilized an attenuated non-pathogenic bacterium Listeria monocytogenes to deliver a highly immunogenic Tetanus Toxoid protein (Listeria-TT), as a neoantigen surrogate, into tumor cells through infection in a metastatic mouse ovarian cancer model (Id8p53-/-Luc). Gemcitabine (GEM) was added to reduce immune suppression. Listeria-TT+GEM treatments resulted in tumors expressing TT and reactivation of pre-existing CD4 and CD8 memory T cells to TT (generated early in life). These T cells were then attracted to the TT-expressing tumors now producing perforin and granzyme B. This correlated with a strong reduction in the ovarian tumors and metastases, and a significant improvement of the survival time compared to all control groups. Moreover, two treatment cycles with Listeria-TT+GEM doubled the survival time compared to untreated mice. Checkpoint inhibitors have little effect on ovarian cancer partly because of low neoantigen expression. Here we demonstrated that Listeria-TT+GEM+PD1 was significantly more effective (efficacy and survival) than PD1 or Listeria-TT+GEM alone, and that more treatment cycles with Listeria-TT+GEM+PD1 significantly increased the survival time compared to Listeria-TT+GEM alone. In summary, the results of this study suggest that our approach may benefit ovarian cancer patients.

Explaining human interactions on the road by large-scale integration of computational psychological theory.

When humans share space in road traffic, as drivers or as vulnerable road users, they draw on their full range of communicative and interactive capabilities. Much remains unknown about these behaviors, but they need to be captured in models if automated vehicles are to coexist successfully with human road users. Empirical studies of human road user behavior implicate a large number of underlying cognitive mechanisms, which taken together are well beyond the scope of existing computational models. Here, we note that for all of these putative mechanisms, computational theories exist in different subdisciplines of psychology, for more constrained tasks. We demonstrate how these separate theories can be generalized from abstract laboratory paradigms and integrated into a computational framework for modeling human road user interaction, combining Bayesian perception, a theory of mind regarding others' intentions, behavioral game theory, long-term valuation of action alternatives, and evidence accumulation decision-making. We show that a model with these assumptions-but not simpler versions of the same model-can account for a number of previously unexplained phenomena in naturalistic driver-pedestrian road-crossing interactions, and successfully predicts interaction outcomes in an unseen data set. Our modeling results contribute to demonstrating the real-world value of the theories from which we draw, and address calls in psychology for cumulative theory-building, presenting human road use as a suitable setting for work of this nature. Our findings also underscore the formidable complexity of human interaction in road traffic, with strong implications for the requirements to set on development and testing of vehicle automation.

Creativity Is Contextual: A Narrative Review of Motor Creativity Tests From an Ecological Perspective.

This narrative review seeks to compare the various ways in which motor creativity has been measured and to critically evaluate those methods within the context of our contemporary understanding of motor creativity. Eligible studies included those of any study design, experimental or observational, as long as motor creativity was measured. Three databases (i.e., PubMed, Scopus, and ScienceDirect) were searched from the earliest possible start dates to December 2021. No risk of bias assessment was performed as the study outcomes were not the focus of the review. After screening for eligibility, 23 articles were included for review, all having measured motor creativity. Of the 23 articles, 16 measured generic motor creativity, while the remaining seven measured task-specific motor creativity. Furthermore, 16 of the studies tested motor creativity with largely static environmental constraints, while the remaining seven were conducted with dynamic environmental constraints. Using a contemporary understanding of motor creativity, most motor creativity tests presently do not possess sufficient task specificity and environmental dynamism, which may not provide an appropriate context for the emergence of creative motor action.

Phytogalactolipids activate humoral immunity against colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the third most lethal cancer in the world, and its incidence is steadily rising. In this study, we investigated the induction of humoral immunity by a phytogalactolipid enriched fraction (CRA) derived from the medicinal plant Crassocephalum rabens (Benth.) S. Moore to combat CRC. METHODS: Immunocompetent BALB/c mice were used to evaluate CRA's therapeutic effects in CRC. The phenotypes of B cell subsets in splenocytes and tumors from the CRA-treated mice were isolated and analyzed by flow cytometry. The titers, isotypes, specificity, antigen recognition, and cytotoxic activity of CRA-induced anti-tumor antibodies were determined. The mechanisms of CRA on B cell differentiation were determined by cell-based analyses, including co-cultural with T cells, cytokine analysis, gene expression by qPCR, and protein expression by western blotting. RESULTS: CRA efficiently inhibited tumor growth in colorectal tumor-bearing allograft mice. CRA treatment attracted an abundance of B cells into the tumor consequently enhancing the anti-tumor antibodies in sera and inducing a class-switch. CRA-induced antisera (designated CRA antisera) specifically recognized surface antigens on the plasma membrane of cancer cells. CRA antisera induced cytotoxicity including antibody-dependent cell cytotoxicity, phagocytosis, and complement-dependent cytotoxicity. CRA interacted with IL-6 receptor to activate STAT3 and cMaf, resulting in T cell secretion of IL-21, which, in turn induced B cell differentiation through the IL-21R/STAT3/Blimp-1 pathway. CONCLUSIONS: CRA regulated T cell activity resulting in B cell activation and triggering of anti-tumor antibodies to impede CRC progression.

In silico analysis to identify miR-1271-5p/PLCB4 (phospholipase C Beta 4) axis mediated oxaliplatin resistance in metastatic colorectal cancer.

Oxaliplatin (OXA) is the first-line chemotherapy drug for metastatic colorectal cancer (mCRC), and the emergence of drug resistance is a major clinical challenge. Although there have been numerous studies on OXA resistance, but its underlying molecular mechanisms are still unclear. This study aims to identify key regulatory genes and pathways associated with OXA resistance. The Gene Expression Omnibus (GEO) GSE42387 dataset containing gene expression profiles of parental and OXA-resistant LoVo cells was applied to explore potential targets. GEO2R, STRING, CytoNCA (a plug-in of Cytoscape), and DAVID were used to analyze differentially expressed genes (DEGs), protein-protein interactions (PPIs), hub genes in PPIs, and gene ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. R2 online platform was used to run a survival analysis of validated hub genes enriched in KEGG pathways. The ENCORI database predicted microRNAs for candidate genes. A survival analysis of those genes was performed, and validated using the OncoLnc database. In addition, the 'clusterProfiler' package in R was used to perform gene set enrichment analysis (GSEA). We identified 395 DEGs, among which 155 were upregulated and 240 were downregulated. In total, 95 DEGs were screened as hub genes after constructing the PPI networks. Twelve GO terms and three KEGG pathways (steroid hormone biosynthesis, malaria, and pathways in cancer) were identified as being significant in the enrichment analysis of hub genes. Twenty-one hub genes enriched in KEGG pathways were defined as key genes. Among them AKT3, phospholipase C Beta 4 (PLCB4), and TGFB1 were identified as OXA-resistance genes through the survival analysis. High expressions of AKT3 and TGFB1 were each associated with a poor prognosis, and lower expression of PLCB4 was correlated with worse survival. Further, high levels of hsa-miR-1271-5p, which potentially targets PLCB4, were associated with poor overall survival in patients with CRC. Finally, we found that PLCB4 low expression was associated with MAPK signaling pathway and VEGF signaling pathway in CRC. Our results demonstrated that hsa-miR-1271-5p/PLCB4 in the pathway in cancer could be a new potential therapeutic target for mCRC with OXA resistance.

Immune response to the mRNA COVID-19 vaccine in hemodialysis patients: cohort study.

Background: End-stage renal disease (ESRD) patients experience immune compromise characterized by complex alterations of both innate and adaptive immunity, and results in higher susceptibility to infection and lower response to vaccination. This immune compromise, coupled with greater risk of exposure to infectious disease at hemodialysis (HD) centers, underscores the need for examination of the immune response to the COVID-19 mRNA-based vaccines. Methods: A transcriptomic analysis of the immune response to the Covid-19 BNT162b2 mRNA vaccine was assessed in 20 HD patients and cohort-matched controls. RNA sequencing of peripheral blood mononuclear cells (PBMCs) was performed longitudinally before and after each vaccination dose for a total of six time points per subject. Anti-spike antibody levels were quantified prior to the first vaccination dose (V1D0) and seven days after the second dose (V2D7) using anti-Spike IgG titers and antibody neutralization assays. Anti-spike IgG titers were additionally quantified six months after initial vaccination. Clinical history and lab values in HD patients were obtained to identify predictors of vaccination response. Results: Transcriptomic analyses demonstrated differing time courses of immune responses, with predominant T cell activity in controls one week after the first vaccination dose, compared to predominant myeloid cell activity in HD at this time point. HD demonstrated decreased metabolic activity and decreased antigen presentation compared to controls after the second vaccination dose. Anti-spike IgG titers and neutralizing function were substantially elevated in both controls and HD at V2D7, with a small but significant reduction in titers in HD groups (p < 0.05). Anti-spike IgG remained elevated above baseline at six months in both subject groups. Anti-spike IgG titers at V2D7 were highly predictive of 6-month titer levels. Transcriptomic biomarkers after the second vaccination dose and clinical biomarkers including ferritin levels were found to be predictive of antibody development. Conclusion: Overall, we demonstrate differing time courses of immune responses to the BTN162b2 mRNA COVID-19 vaccination in maintenance hemodialysis subjects (HD) comparable to healthy controls (HC) and identify transcriptomic and clinical predictors of anti-Spike IgG titers in HD. Analyzing vaccination as an in vivo perturbation, our results warrant further characterization of the immune dysregulation of end stage renal disease (ESRD). Funding: F30HD102093, F30HL151182, T32HL144909, R01HL138628This research has been funded by the University of Illinois at Chicago Center for Clinical and Translational Science (CCTS) award UL1TR002003.

Trimer IgG and neutralising antibody response to COVID-19 mRNA vaccination in individuals with sarcoidosis.

Background: Individuals with sarcoidosis are at higher risk for infection owing to underlying disease pathogenesis and need for immunosuppressive treatment. Current knowledge as to how subjects with sarcoidosis respond to different forms of vaccination is limited. We examined quantitative and functional antibody response to COVID-19 vaccination in infection-naive subjects with and without sarcoidosis. Methods: Our prospective cohort study recruited 14 subjects with biopsy-proven sarcoidosis and 27 age-sex matched controls who underwent a two-shot series of the BNT162b2 mRNA vaccine at the University of Illinois at Chicago. Baseline, 4-week and 6-month trimer spike protein IgG and neutralising antibody (nAb) titres were assessed. Correlation and multivariate regression analysis was conducted. Results: Sarcoidosis subjects had a significant increase in short-term antibody production to a level comparable to controls; however, IgG titres significantly declined back to baseline levels by 6 months. Corresponding neutralising assays revealed robust nAb titres in sarcoidosis subjects that persisted at 6 months. A significant and strong correlation between IgG and nAb titres across all time points was observed in the control group. However within the sarcoidosis group, a significant but weak correlation between antibody levels was found. Overall, IgG levels were poor predictors of nAb titres at short- or long-term time points. Conclusions: Sarcoidosis subjects exhibit nAb induced by the BNT162b2 mRNA SARS-CoV-2 vaccine at levels comparable to controls that persists at 6 months indicating conferred immunity. Trimer IgG levels are poor predictors of nAb in subjects with sarcoidosis. Studies of further antibody immunoglobulins and subtypes warrant investigation.

Infective endocarditis after surgical aortic or mitral valve replacement: A nationwide population-based study.

OBJECTIVE: Evidence regarding the incidence of prosthetic valve endocarditis and its association with the use of mechanical or biologic prosthetic valves is limited. METHODS: Patients who underwent aortic or mitral valve replacement in the years 2000 to 2017 were identified from Taiwan's National Health Insurance Research Database and grouped according to the type of prosthesis used (mechanical or biologic). Propensity score matching was performed to reduce confounding. RESULTS: A total of 22,844 patients were included, with 11,950 (52.2%) and 10,934 (47.8%) in the mechanical prosthesis and biologic prosthesis groups, respectively. After matching, each group contained 5441 patients. During follow-up, patients with a biologic prosthesis had a significantly higher risk of infective endocarditis (IE) than those with a mechanical valve (3.4% vs 1.9%; subdistribution hazard ratio, 1.78; 95% CI, 1.40-2.26). Moreover, biologic prostheses were associated with greater risks of all-cause mortality and redo valve surgery, but lesser risks of ischemic stroke, hemorrhagic stroke, major bleeding, and gastrointestinal bleeding. In subgroup analysis, biologic prostheses were consistently associated with a greater risk of IE in all subgroups, specifically single-valve replacement-aortic, single-valve replacement-mitral, double-valve replacement, active IE (IE diagnosed during index hospitalization), any IE (active or old), and not having a history of IE. CONCLUSIONS: In this nationwide population-based retrospective cohort study, biologic prosthesis use was associated with a greater risk of IE during follow-up compared with mechanical valve use. However, mechanical valve use was associated with a greater risk of ischemic stroke and hemorrhagic complications.